Abstract

Aging is associated with negative health consequences, including increased adiposity and decreased muscle mass. Although age is a dominant risk factor for numerous common diseases, including coronary artery disease, diabetes, and cancer, the underlying mechanism for the metabolic changes associated with aging is unknown. Park et al. endeavored to understand how metabolism and physical fitness decline with age.

DNA dependent protein kinase (DNA-PK) is an enzyme that is activated by damage to DNA, an occurrence that increases with age. DNA-PK phosphorylates the chaperone protein HSP90α, disrupting the ability of HSP90α to complex with enzymes such as AMP-activated protein kinases (AMPK). AMPK is critical for mitochondrial biogenesis and energy metabolism. The authors demonstrated that DNA double-stranded breaks and phosphorylated (active) DNA-PK were increased dramatically in middle-aged rhesus macaque skeletal muscle cells compared with young muscle cells. They then hypothesized that blocking DNA-PK would result in increased AMPK and protect against the metabolic effects of aging. Severe combined immunodeficiency (SCID) mice, which carry a mutation in DNA-PK, and a highly specific DNA-PK inhibitor were used to test this hypothesis.

This study presents a possible mechanism for the deleterious metabolic changes associated with aging. Inhibiting the DNA-PK pathway may ameliorate obesity, insulin resistance, and loss of physical fitness. It is possible that DNA-PK inhibitors may have therapeutic potential in treating the weight gain and decreased exercise capacity common in aging patients.